Comorbidity of Alcohol Use Disorder (AUD) with schizophrenia (SZ) is highly prevalent at over 33% of SZ patients. Comorbidity is associated with particularly unfavorable outcomes including increased mortality risk and treatment non-adherence. Of particular relevance, some SZ patients have reported a decrease in negative symptoms following alcohol ingestion. This is important because the negative symptoms of SZ (loss of motivation, flattening of emotional responses, decreased speech and activity, and social withdrawal), are disabling and persistent, and significantly contribute to the immense personal and economic costs of SZ. No medications are FDA-approved for treatment of negative symptoms in SZ. Proline is a precursor of the neurotransmitter glutamate and may function as a CNS neuromodulator. Elevated proline stimulates dopamine (DA) signaling in murine models. The Catechol-O-methyltransferase (COMT) enzyme catalyzes deactivation of neurotransmitters including DA. In our recent, replicated study we found that fasting plasma proline levels (which reflect CNS levels) and the COMT Val158Met functional polymorphism (a well characterized marker of DA metabolism due to the encoded high or low activity enzyme) significantly interact, predicting negative symptom outcomes in patients with severe psychiatric illness. Specifically, in Val/Val high enzyme activity patients, high proline is protective with low negative symptom severity or a greater negative symptom reduction over time. Conversely, COMT Met carriers (low activity) demonstrated the opposite: Significantly more negative symptoms or less symptom improvement as proline increased. Alcohol ingestion upregulates circulating proline in those with a current or past AUD, and thus we hypothesized that comorbid patients self-medicate with alcohol to relieve their negative symptoms; predicting more frequent comorbid AUD in Val/Val SZ patients. In a preliminary study we indeed found a strong trend for a higher proportion of AUD in Val/Val?s, as compared to Met carriers for whom alcohol-induced proline elevation would be detrimental (p=0.065 two-tailed). Taken together, our findings are important because there are medications that up-regulate proline levels, such as valproate (VPA), prescribed to ~35% of SZ inpatients. We propose that personalized VPA treatment in comorbid AUD and SZ Val/Val patients, may relieve negative symptoms and assist in maintaining abstinence due to this relief. As a necessary prerequisite to an RCT of VPA, the work described under this exploratory R21 study should allow us to move towards such a personalized treatment approach: Specific Aim 1: We will confirm our preliminary study, powered to show association of COMT with AUD in SZ; Specific Aim 2: In a naturalistic, longitudinal setting we will test the innovative hypothesis that COMT Val/Val SZ patients with co-morbid AUD, have greater negative symptom improvement if they are treated with VPA (because of significant proline elevation), compared to those without an AUD and non-VPA treatment groups; Exploratory Aim 3: To test for a VPA response on alcohol use outcomes in SZ outpatients.